SLE and Kidney Disease in 2014
GERALD APPEL, MD
Professor of Clinical Medicine Columbia University –College of Physicians and Surgeons NY-Presbyterian Hospital New York, New York
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)
• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
Where can one find a kidney?
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
ISN/RPS Classification of LN• Class I Minimal mesangial LN• Class II Mesangial proliferative LN• Class III Focal LN III (A): Active lesions: focal proliferative LN III (A/C): Active and chronic lesions III (C): Chronic inactive lesions with scars• Class IV Diffuse LN IV-S (A): Active lesions: diffuse segmental proliferative LN IV-G (A): Active lesions: diffuse global proliferative LN IV-S (A/C): Active and chronic lesions IV-G (A/C): Active and chronic lesions IV-S (C): Chronic inactive lesions with scars IV-G (C): Chronic inactive lesions with scars • Class V Membranous LN• Class VI Advanced sclerotic LN
ISN = International Society of Nephrology; RPS = Renal Pathology Society
Lupus Nephritis Class ILupus Nephritis Class I
Lupus Nephritis Class IILupus Nephritis Class II
Lupus Nephritis Class IIILupus Nephritis Class III
Histology WHO Class IV: Diffuse Endocapillary Proliferation With Karyorrhexis and Focal Necrosis
Focal Necrosis Endocapillary Proliferation
Lupus Nephritis Class IVLupus Nephritis Class IV
Pre-Rx Post-Rx
Lupus Nephritis Class IVLupus Nephritis Class IV
Lupus Nephritis Class VLupus Nephritis Class V
End stage kidney due to chronic GN: Diffuse and global glomerulosclerosis, tubular atrophy & interstitial fibrosis
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
Case 3: Saleswoman with rash and arthritis
•A 29 year old saleswoman develops arthritis
multiple joints, fever•Exam: Lymphadenopathy, and a malar rash.•Labs:
–Urinalysis 3+ protein, 18-20 rbc’s–Creatinine 1.2 mg/dl–24 hr. protein 1.8 g per day –Complement 18% (normal 50-150%)–ANA positive, Anti-DNA antibody positive
KIDNEY BIOPSY PERFORMED
RBC cast forms a mold of tubular lumen
Diffuse proliferative lupus nephritis: Diffuse and global mesangial and glomerular capillary wall positivity for IgG
Full house IF staining: IgG, IgM, IgA, C3, C1q
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• What happened with SLE Kidney disease ( lupus nephritis )in
the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
Event Cy Therapy
(n = 21)Combination Therapy
(n = 20)
n/n n/n
Hypertension 10/20 10/20
Ischemic heart disease 1/19 4/19
Hyperlipidemia 7/20 8/19
Valvular heart disease 9/19 7/21
Avascular necrosis 6/21 6/20
Osteoporosis 4/18 3/19
Premature menopause 9/16 10/18
Major infections 7/21 9/20
Herpes zoster infection 6/21 5/20
Side Effects of Cyclophosphamide in the past
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
MMF +
glucocorticoids (e.g. pulse methylprednisolone)
CYC +
Glucocorticoids(e.g. pulse methylprednisolone)
or
EURO LUPUSLow-dose CYC
NIH studyHi-dose CYC
or
6 months 6 months
INDUCTION
Proliferative LN ACR- KDIGO Treatment guidelines –
CONFIDENTIALAnti-MIF & LN Ad Board, July 13, 2011
Proliferative Lupus Nephritis – Maintenance TreatmentACR – KDIGO Treatment guidelines
IMPROVED NOT IMPROVED
MMFinduction
MMF1-2g/dor
AZA 2 mg/kg/d ± lo dose daily GC
CYC (lo- or hi-dose)
+pulse GC then
daily GC 6 m
onth
s
CYCinduction
IMPROVED NOT IMPROVED
MMF1-2g/dor
AZA 2 mg/kg/d ± lo dose daily GC
MMF 2-3g/d x 6 months
+pulse GC then daily
GC 6 m
onth
s
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
ELNT - 10 year FU - ESRD
Houssiau FA et al. Ann Rheum Dis 2009,
ELNT - 10 year FU
Houssiau FA et al. Ann Rheum Dis 2009, Jan 20 (Epub ahead of print)
ALMS TRIAL Primary Endpoint: Responders at Month 6
56.2% 53.0%
0
20
40
60
80
100
Prop
ortio
n of p
atien
ts rep
ondin
g (%
)
Response judged by blinded Clinical Endpoint Committee:
Decrease in proteinuria to <3g if baseline nephrotic (≥3g/d) , or by ≥50% in patients ith subnephrotic (<3g/d) proteinuria
and
Stabilization of serum creatinine level (24-week level ± 25% of baseline),or improvement
MMF was not superior to IVC (p = 0.575)
MMF
IVC
Appel , Contreras, Dooley et al JASN 2009
0
20
40
60
80
100
120
140
160
Seru
m c
reati
nin
e (μ
mol/
L,
SD
)IVCMMF
ALMS Trial - Renal Variables
0
1
2
3
4
5
6
7
8
9
Baseline 4 8 12 16 20 24 Endpoint
24
ho
ur
uri
ne p
rote
in (
g/
day,
SD
)
Week
Serum creatinine and urine protein levels improved in both the MMF and IVC groups
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.
Rituximab:Anti-CD20 Monoclonal Antibody
Rituximab - FDA approved for the treatment of relapsed or refractory, CD20-positive B-cell NHLymphomas
• Approved for Rheumatoid Arthritis – used in 240,000 patients > 10 yrs
• Approved for ANCA+ glomerulonephritis since 2010
• Chimeric murine/human monoclonal antibody
Davies B, Shaw T. Presented at EULAR 2004.
Maloney DG, et al. J Clin Oncol. 1997;15(10):3266-3274.
Rituxilup Trial
• MPred + MMF + Rituximab vs MP + MMF + steroids ( ALMS regimen )
• 19 Adult + 4 Peds Centers in UK; Europe 12 Centers in 3 networks; US Centers.
• Non-inferiority Trial of 252 LN patients • Primary endpoint complete remission at 1 yr.• Secondary Endpoints – Time to CR, Partial
remissions, PR with histologic response, serious infections, SAEs, SRI score etc.
Navarra, et al. Lancet. 2011;377(9767):721-31Furie, et al. Arthritis Rheum. 2011;63(12):3918-30
1 mg/kg belimumab
60
40
20
0
0 4 8 12 16 20 24 28 32 36 40 44 48 52Visit Week
SR
I R
esp
on
der
s (%
)
+ + +*
+*
+*
+*
+*
+*
+*
* p<0.05 + p<0.05
10 mg/kg belimumabPlacebo
50
40
30
20
10
0
0 4 8 16 24 32 40 48 52 60 68 76
Visit Week
% S
RI
Res
po
nd
ers *
Belimumab – FDA Approved for SLE
p<0.05
SRI, SLE Responder Index
IMNL-SCT-019799
Abatacept ( CTLA4Ig Co-Stimulatory Blocker ) Study in 300 LN PTS
Background Rx: MMF up to 3 g/day plus corticosteroids
Primary Outcome Measure: Time to complete response
Abatacept 10/1010 mg/kg days 1,15, 29, then Q 28 days
Abatacept 30/1030 mg/kg x4, then 10 mg/kg Q 28 days
Placebo
Days 1 and 15(1st and 2nd dose)
Day 337Final dose
Dose every 28 days
Randomization1:1:1
Courtesy of D Wofsy
Treatment of LN with Abatacept and Low-Dose Pulse Cyclophosphamide: The ACCESS TrialBrad H. Rovinon behalf of the ACCESS Trial Group
• EuroLupus Low dose Cyclophosphamide and prednisone starting at 60 mg (tapering to 10 mg by week 12 )
• Azathioprine 2 mg/kg/day PO maintenance
• Abatacept 500 mg or 1000 mg at 0, 2, 4, then Q4 wk until week 24 vs Placebo
Proteasome Inhibitors
NH
HN BO
OHOH
O
N
N
Bortezomib
( Velcade™)
Carfilzomib
(Kyprolis)
Manufacturer Takeda Onyx/Amgen
Status Approved Approved
Indications Myeloma & Mantle Cell Lymphoma Myeloma & Solid Tumors
Class Boronic Acid Ketoepoxide
Active Sites Targeted
b5/LMP7/LMP2 b5/LMP7
Bortezomib for NZB/W F1: Kidney Disease
Neubert Nat. Med. 2008
An Open Label Randomized Phase IV Study of the Safety and Efficacy of ACTHAR GEL in Patients with Membranous
(Class V) Lupus NephritisPrincipal Investigator: Brad H. Rovin MD, Ohio State University
SCRN 0 1 2 3 4 5 6 9 12
Study Month
ARM 1. Acthar Gel 80 IU administered subcutaneously 2 times per week, 12 patients
ARM 2. Acthar Gel 80 IU administered subcutaneously 3 times per week, 13 patients
Administration of Acthar Follow-Up
Primary Objectives: • To determine the safety and tolerability of Acthar Gel in patients with Class V lupus
nephritis• To determine the efficacy of Acthar Gel in patients with Class V lupus nephritis as
CRR+PRR
Treatment of Severe LN in the Future
• Treatment will still be divided into an induction and maintenance phase.
• Induction therapy will consist of Cyclophosphamide (usually IV ) or MMF or Newer regimens e.g. older drugs combined with CNI’s, ACTH, proteosome inhibitors, or corticosteroid free Rituximab regimens.
• Maintenance therapy will consist of MMF or AZA or rituximab or other newer agents .
• Use of combinations of immunosuppressives will increase.• One Regimen Will Not Fit All
Lupus and Kidney Disease
• What are the kidneys – how do they work? ( what is a nephrologist?)• How does SLE involve the kidneys?• How do you know if you have kidney involvement?• Are there different patterns of Kidney disease with SLE?• What happened with SLE Kidney disease ( lupus nephritis )in the past ?• Can we treat kidney disease due to LN today?• How successful are we?• Will there be new ways to treat it tomorrow.